The field of the invention is delivery of vaccines.
Bacterial and viral diseases have long plagued mankind. Bacterial diseases include tuberculosis, typhoid, pneumonia, meningitis, pertussis, diphtheria, cholera, streptococcal infections and other disabling or potentially fatal diseases. Some of the more common or better known viral diseases are chicken pox, measles, mumps, rubella, influenza, parainfluenza, hepatitis, HIV/AIDS and the diseases associated with rotavirus, cytomegalovirus, herpes simplex, respiratory syncytial, and Epstein-Barr viruses. Many of these bacterial or viral diseases are highly contagious, difficult to treat or cure, or have treatments or cures involving serious undesirable side effects.
Modern medicine has provided vaccines targeted at many of these bacterial and viral diseases. The vaccines work by inducing the body (human or animal) to produce antibodies, so that the body better resists infection when subsequently exposed to the bacteria or virus. In addition, therapeutic vaccines are currently in development to treat chronic ailments such as autoimmunity, hypertension, cancer and even drug addiction.
Various forms of vaccine have been used to combat these diseases. The common forms of vaccines are live attenuated vaccines, including bacteria and viruses (RNA or DNA-based), killed organism vaccines, polypeptide-based vaccines, polysaccharides, conjugated polysaccharides and inactivated toxins. In addition, vaccines in development include naked DNA vaccines and genetically engineered organisms or hybrids.
Conventionally, vaccines have been prepared as a reconstituted liquid and injected into the patient using a syringe. Unfortunately, this delivery technique has several disadvantages. Initially, delivering a vaccine via injection with a syringe involves the risk inherent in using needles. Specifically, under certain conditions, there is risk of transmission of disease via the injection, due to contamination with blood borne pathogens such as HIV, hepatitis B, HCV, etc. The risk of such contamination is significant, especially in developing countries. The World Health Organization estimates that up to one-third of all injections given in developing countries are unsafe.
Vaccine delivery by injection is often also perceived to be painful, especially by children, thereby resulting in potentially uncooperative patients. Delivery by injection also requires that the practitioner providing the injection have a measure of skill and training.
In efforts to overcome these disadvantages, various proposals have been made for delivering vaccines to the lung with some form of nebulizer or metered-dose inhaler. In these proposals, the liquid suspension vaccine is dispersed into a cloud of tiny droplets, which are then inhaled by the patient. Some of these proposals have recognized the advantages in providing an enhanced local respiratory tract immunity, especially against diseases active in the lungs. Studies on vaccines delivered in nebulized forms show that patient""s immune response resulting from delivery of a vaccine to the lung, equals or exceeds the immune response created by vaccine injection.
However, notwithstanding these results, vaccines continue to be delivered primarily via injection, apparently due to reasons of cost, convenience, and complexity of operating metered-dose inhalers and nebulizers.
Accordingly, there is a need for improved methods for providing a vaccine to a patient via the lung, to create an immune response.
To this end a vaccine is provided as a dry powder formulation, via inhalation. This pulmonary delivery of a vaccine as a dry powder for inhalation has the potential to address several critical issues: (1) the need to increase biological efficacy by providing a vaccine that better confers local mucosal immunity as well as systemic immunity, (2) the need to increase safety during administration by eliminating the potential contamination risks associated with needles, (3) the need to increase stability during administration and transport of vaccines and (4) the need to improve cost effectiveness.
Pulmonary delivery of a xe2x80x98localxe2x80x99 dose refers to topical administration to the lung as is typically used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. In the context of immunization, delivery of a local dose of vaccine is appropriate and sufficient to induce protective immunity against pathogens that naturally enter the body via the nose or mouth. Alternatively, a systemic dose typically describes administration via the lung for absorption from the alveolar region to the circulation to treat systemic disorders, such as diabetes, migraine, osteoporosis, and hormone regulation. For example, to generate protection against blood borne pathogens, a systemic dose of vaccine may be required. Increased protection may be achieved by producing a vaccine that targets both local and systemic delivery. The choice or balance achieved between local and systemic dose impacts the approach taken to formulate the dry powder for inhalation. The two main factors to be considered are the anatomy of the lung and aerosol dynamics.
As the airways of the lung become smaller and more highly branched, they become increasingly difficult to penetrate with aerosol. To optimize deposition in either (1) the Oropharyngeal/tracheobronchial region for a local dose or (2) the bronchial/pulmonary region for a systemic dose, a key parameter to control is particle size. It is generally accepted that for particles with aerodynamic diameters less than 5 microns, the greatest fractional deposition is in the bronchial/pulmonary region of the lung. Deposition in the Oropharyngeal/tracheobronchial region occurs with particles ranging from approximately 5 to 100 xcexcm. For some diseases, such as measles, vaccine particle sizing may not be critical since the CD46 receptors that are recognized by the measles virus are virtually ubiquitous, being expressed by almost all cells except erythrocytes and some bone marrow cells.